ClinVar Miner

Submissions for variant NM_001330504.1(ALG1):c.854+3A>G (rs369160589)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000209837 SCV000265560 likely pathogenic Congenital disorder of glycosylation type 1K 2017-02-09 criteria provided, single submitter research
GeneDx RCV000413040 SCV000491480 likely pathogenic not provided 2016-12-15 criteria provided, single submitter clinical testing The c.1187+3A>G variant in the ALG1 gene has been reported previously in association with congenital disorder of glycosylation, in an affected individual who was heterozygous for the c.1187+3A>G variant and another variant (Ng et al., 2016). This variant is predicted to destroy the natural splice donor site in intron 11, and is expected to cause abnormal gene splicing. The c.1187+3A>G variant was not observed at any significant frequency in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1187+3A>G as a likely pathogenic variant.
Undiagnosed Diseases Network,NIH RCV000209837 SCV000746579 likely pathogenic Congenital disorder of glycosylation type 1K 2017-06-23 criteria provided, single submitter clinical testing Clinical genome sequencing revealed 3 variants of uncertain significance in the ALG1 gene. Multiple lines of computational evidence support a deleterious effect of these variants on the gene or gene product. cDNA experiments performed on a research basis demonstrated that the paternally inherited variant (c.1187+3A>G) is damaging. The maternally inherited variants are rare and are not present in the 1000 Genomes Project nor the Exome Aggregate Consortium (ExAC) databases. Based on these findings, the clinical team elevated these variants to likely pathogenic.
Invitae RCV000209837 SCV000827732 likely pathogenic Congenital disorder of glycosylation type 1K 2018-07-03 criteria provided, single submitter clinical testing This sequence change falls in intron 11 of the ALG1 gene. It does not directly change the encoded amino acid sequence of the ALG1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs369160589, ExAC 0.02%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with congenital disorders of glycosylation (PMID: 26931382, 28554332). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 224118). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant causes the retention of ALG1 intron 11, resulting in a stop gain after adding 84 nucleotides (PMID: 28554332). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000209837 SCV000893400 likely pathogenic Congenital disorder of glycosylation type 1K 2018-10-31 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000209837 SCV001164452 pathogenic Congenital disorder of glycosylation type 1K 2018-12-03 criteria provided, single submitter research The homozygous c.1187+3A>G variant in ALG1 was identified by our study in one individual with congenital disorder of glycosylation. The c.1187+3A>G variant in ALG1 has been reported in 1 individual with congenital disorder of glycosylation (PMID: 26931382), and has been identified in 0.01906% (24/125942) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs369160589). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency and the presence of this variant in combination with a reported pathogenic variant and in an individual with congenital disorder of glycosylation increases the likelihood that the c.1187+3A>G variant is pathogenic (PMID: 26931382; Variation ID: 4724). This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing and cDNA analysis by the NIH Undiagnosed Diseases Network demonstrated this variant has a damaging effect (Variation ID: 224118). A biomarker for loss of function in ALG1, xeno-tetrasaccharide, was detected in the serum of an individual with this variant in the compound heterozygous state (PMID: 26931382). Loss of function of the ALG1 gene is an established disease mechanism in autosomal recessive congenital disorder of glycosylation and there is evidence that this gene is necessary for survival (PMID: 26931382). However, these types of assays may not accurately represent biological function and this information is not predictive enough to determine pathogenicity. This variant has also been reported as likely pathogenic in ClinVar by multiple submitters (Variation ID: 224118). Two additional variants in this splice region have been reported pathogenic in ClinVar, raising the possibility that this splice region is a mutational hot spot (Variation ID: 95934, 194107). In summary, this variant meets criteria to be classified as pathogenic for congenital disorder of glycosylation in an autosomal recessive manner based on the predicted impact of the variant and our findings in the literature and ClinVar. ACMG/AMP Criteria applied: PM2, PM3, PS3, PVS1, PM1_Supporting (Richards 2015).
University of Washington Center for Mendelian Genomics,University of Washington RCV000851246 SCV000993498 likely pathogenic Congenital disorder of glycosylation 2017-05-25 no assertion criteria provided research

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